PROJECT SUMMARY/ABSTRACT Increasing opioid use in the U.S. has led to a dramatic increase in opioid-related fatal and non-fatal overdoses (OD), and adults with mental health disorders, including anxiety and mood disorders, are significantly more likely to use nonprescription opioids. Mental health and associated drug use are directly and significantly impacted by the neighborhood environment, but few studies have examined the impact of modifiable neighborhood features on OD risk. The broad objective of this study is to investigate modifiable neighborhood factors which impact mental health and which may contribute to opioid OD. The proposed research will achieve the following interconnected specific aims using mixed quantitative/qualitative approaches with fatal OD data from New York City, Chicago, and Seattle and original in-depth interviews with people who use drugs: (1) investigate the associations between modifiable physical and social neighborhood factors and opioid OD; (2) examine key mental health indicators as mediators of the relationship between modifiable neighborhood factors and opioid OD; (3) comparatively investigate the associations between modifiable neighborhood factors, mental health indicators, and opioid OD, comparing the locations where people who use opioids lived versus the locations where they overdosed. In-depth interviews with people who use drugs will provide context for quantitative results, identifying mechanisms by which neighborhood impacts drug using and associated OD risk and informing novel strategies for OD prevention. This K01 mentored research scientist development proposal will provide the training and expertise needed to transition to research independence in drug use research. Five specific training areas will be incorporated to carry out these research goals: (1) obtain advanced skills in structural equation modeling and Bayesian modeling methods, and causal inference theory and methods; (2) develop expertise in mixed quantitative and qualitative methods research theory, design, and analysis, and build capacity in collecting and analyzing qualitative data; (3) develop subject matter expertise in psychiatric epidemiology and associated drug use risk factors, in particular, major depression, general anxiety disorders, and diagnostic criteria for psychiatric disorders; (4) obtain additional training in the ethical conduct of research among marginalized and stigmatized populations; (5) build professional skills for a successful research career as an independent scientist leading multidisciplinary teams to build new knowledge and address major challenges in drug use and abuse. These training goals will be achieved through a combination of didactic courses, specialized workshops, hands-on research, and mentoring from an interdisciplinary team of experts. This research and training will lead to a subsequent R01 proposal that formally tests implementation strategies and effectiveness of neighborhood-level interventions for OD prevention.